Mucins are high molecular weight glycoproteins that are involved in many biological functions. MUC 4, a member of the transmembrane mucin family, encodes a human epithelial mucin that is expressed in numerous epithelial tissues and is found in bodily fluids such as saliva, tears, and breast milk. Additionally, MUC4 is expressed in undifferentiated cells of the embryo and fetus. Human MUC4 has been found to contain two subunits, MUC4α and MUC4β. While the MUC4α subunit is largely extracellular, MUC4β is a transmembrane domain that has many implications in cell signaling in both normal and carcinogenic situations.
There are numerous studies that clearly establish the involvement of MUC4 with the progression of cancer and metastasis. Due in part to the fact that MUC4 contains extracellular domains, it has been proposed that MUC4 has a direct role in cell signaling pathways and subsequent behavior of tumor cells. One particular area of interest is the role MUC4 and oncogenesis. In recent studies, MUC4 was ectopically expressed in fibroblast cells resulting in enhanced levels of oncoprotein ErbB2 and tumor formation in nude mice. MUC4β is composed of two domains that are similar to epidermal growth factor, a transmembrane sequence and may have the ability to bind the receptor tyrosine kinase. This suggests that MUC4 plays a distinct role as a ligand in ErbB2 cell signaling likely by stabilizing and enhancing the activity of ErbB2 growth factor receptor. In addition to ErbB2, silencing of MUC4 in pancreatic cancer cells was associated with down regulation of HER2 and a subsequent reduction in its ability to contribute to tumorgenesis. MUC4 also contains a heavily glycosylated tandem repeat domain which provides structural rigidity to the extended cellular region thus serving as a barrier for some cell-cell and cell-extracellular matrix interactions subsequently allowing it to act as a reservoir for certain growth factors.
Further evidence for the relationship between MUC4 and growth factor signaling is seen in the fact that the MUC4 promoter region contains binding sites for different transcription factors such as interferon-Γ, retinoic acid and transforming growth factor-13 that in turn are responsible for the regulation of its expression in different tissues.